The objective of the project is to translate a phase-sensitive x-ray tomosynthesis technique to clinical practice to reduce radiation dose and improve accuracy in breast cancer diagnosis. The technique is based on the principle of inline phase-sensitive x-ray imaging operating at high energies of 120 to 150 kVp. We will build a patient imaging system and conduct preclinical evaluations and phase 1 clinical trial. As the result of more than 20 years of research, digital breast tomosynthesis (DBT) was recently approved by the FDA and introduced into clinical practice. The key advantage of DBT as compared with projection mammography is its 3D capability that effectively removes the superimposed breast parenchymal structures and improves the conspicuity and detection of breast cancer. However, there are two main limitations with DBT. The first regards its ability to detect subtle breast calcifications, and the second involves the higher radiation dose as compared with conventional mammography. It is therefore necessary to improve the sensitivity and specificity of DBT and reduce the radiation dose to patients. It has been shown that tissue- lesion contrast based on x-ray phase-shifts is greater than the corresponding attenuation contrast. In addition, while low x-ray energies must be used in conventional attenuation-based breast imaging, high x-ray energies can be used in phase-sensitive imaging to reduce the radiation dose. We therefore propose the integration of innovative phase-sensitive methods with DBT. The hypothesis of our proposal is that high energy phase-sensitive breast tomosynthesis (PBT) can greatly enhance tissue contrast and significantly reduce radiation dose as compared to current digital breast tomosynthesis (DBT). To test our hypotheses, we will (1) assemble a high energy (120-150 KV) x-ray phase- sensitive breast tomosynthesis system with a micro-focus tube source and a high-resolution flat panel detector; (2) optimize the phase retrieval algorithm and test it under clinical patient imaging conditions; (3) characterize the performance of the patient imaging system and its key components for system optimization, and compare the proposed system with DBT to determine radiation dose savings; (4) conduct subjective preclinical evaluations with cadaver and other phantoms to determine the optimal operating parameters for patient studies; (5) conduct a Phase 1 clinical evaluation and statistical analysis with 110 patients to compare phase- sensitive and conventional tomosynthesis systems. The proposed research will facilitate the translation of this innovative phase-sensitive breast tomosynthesis technique to clinical practice, and enhance the sensitivity and specificity of breast cancer detection while also reducing the radiation dose.